The present invention relates to compounds that can be used to treat or prevent inflammatory diseases or atherosclerosis. The present invention also relates to pharmaceutical compositions that can be used to prevent or treat inflammatory diseases or atherosclerosis, and to methods of treating and preventing inflammatory diseases or atherosclerosis. In particular, the compounds of the present invention are inhibitors of the enzyme 15-lipoxygenase and are inhibitors of monocyte chemotaxis.
Atherosclerosis is a multifactorial disease characterized by excessive intracellular lipid deposition in macrophages, leading to the formation of foam cells. The accumulation of lipid-loaded foam cells in the subendothelial space leads to formation of fatty streaks, which are the early atherosclerotic lesions. Oxidative modifications of lipids, specifically low-density lipoprotein, has been implicated as a major process in foam-cell formation.
Lipoxygenases are nonheme iron-containing enzymes that catalyze the oxygenation of certain polyunsaturated fatty acids such as lipoproteins. Several different lipoxygenase enzymes are known, each having a characteristic oxidation action. One specific lipoxygenase, namely 15-lipoxygenase (15-LO), has been detected in atherosclerotic lesions in mammals, specifically rabbit and man. The enzyme, in addition to its role in oxidative modification of lipoproteins, is important in the inflammatory reaction in the atherosclerotic lesion. Indeed, 15-LO has been shown to be induced in human monocytes by the cytokine IL4, which is known to be implicated in the inflammatory process.
Inhibitors of 15-LO are especially useful to prevent and treat inflammatory diseases such as asthma, psoriasis, arthritis, and atherosclerosis. While there are several lipoxygenase enzymes, specific inhibition of 15-LO is important in the inflammatory and atherosclerosis process. A characteristic feature of atherosclerosis is the accumulation of cholesterol ester engorged foam cells. Foam cells are derived from circulating monocytes that invade artery walls in response to hypercholesterolemia, and mature into tissue macrophages. The enzyme 15-LO has been implicated in inflammatory disorders and in the origin and recruitment of foam cells (See Harats, et al., Trends Cardiovasc. Med., 1995;5(1):29-36). This enzyme is capable of oxidizing esterified polyenoic fatty acids, such as those found in phospholipids. Treatment of experimental animals with antioxidants which reduced hydroperoxides produced by 15-LO has been shown to retard the progression of atherosclerotic lesions. For example, Sendobry, et al., British Journal of Pharmacology, 1997;120:1199-1206 show suppression of atherogenesis in rabbits fed a high-fat diet and treated with a 15-LO inhibitor.
The present invention provides compounds having the Formula I 
heteroaryl, substituted heteroaryl, xe2x80x94NRxe2x80x2Rxe2x80x2, or cycloalkyl;
each Rxe2x80x2 is independently hydrogen or C1-C6 alkyl;
Re is 
xe2x80x83C1-C18 alkyl, heteroaryl, substituted heteroaryl, naphthyl, benzyl, or dansyl;
each of R1, R2, R3, R4, R5, R7, R8, R9, Ra, Rb, Rc, and Rd are independently hydrogen, xe2x80x94OC1xe2x80x94C6 alkyl, xe2x80x94SC1xe2x80x94C6 alkyl, halogen, C1-C6 alkyl, xe2x80x94OH, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94OCF3, xe2x80x94CO2C1xe2x80x94C6 alkyl, xe2x80x94SO3H, xe2x80x94SO3-alkali metal, xe2x80x94NH2, xe2x80x94NHC1xe2x80x94C6 alkyl, 
xe2x80x83xe2x80x94CO2C1xe2x80x94C6 alkyl, xe2x80x94SO3H, xe2x80x94SO3 alkali metal, xe2x80x94CN, xe2x80x94CH2-halogen, 
xe2x80x83heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, benzoyl, 
xe2x80x83xe2x80x94SO3H, xe2x80x94SO3NRxe2x80x2Rxe2x80x2, xe2x80x94CHO, xe2x80x94SO2NH2, or xe2x80x94NRxe2x80x2Rxe2x80x2; or the pharmaceutically acceptable salts thereof, provided that when Y is 
xe2x80x83Q is not C1-C6 alkyl; further provided that when X is 
xe2x80x83and Y is xe2x80x94NH, Rb is not xe2x80x94OH; further provided that when X and Y are 
xe2x80x83Re and Q are not unsubstituted phenyl; further provided that when Y is 
xe2x80x83Re and Q are not both aryl; further provided that when Y is xe2x80x94SO2NHxe2x80x94 or xe2x80x94SO2NC1xe2x80x94C6 alkyl and X is 
xe2x80x83Q and Re are not both unsubstituted phenyl; further provided that when Y is 
xe2x80x83Re is unsubstituted phenyl di- or tri-substituted phenyl; further provided that when Y is 
xe2x80x83Q is not unsubstituted aryl.
In a preferred embodiment of the compounds of Formula I, X is 
In another preferred embodiment of the compounds of Formula I, Rxe2x80x2 is hydrogen or methyl.
In another preferred embodiment of the compounds of Formula I, X is xe2x80x94Oxe2x80x94.
In another preferred embodiment of the compounds of Formula I, X is 
In another preferred embodiment of the compounds of Formula I, Rxe2x80x2 is hydrogen.
In another preferred embodiment of the compounds of Formula I, Rc is xe2x80x94OCH3, hydrogen, xe2x80x94OCH2CH3, halogen, -S-methyl, or xe2x80x94OCF3.
In another preferred embodiment of the compounds of Formula I, Y is 
In another preferred embodiment of the compounds of Formula I, X is 
In another preferred embodiment of the compounds of Formula I, Y is 
In another preferred embodiment of the compounds of Formula I, Rc is hydrogen, hydroxy, xe2x80x94OC1xe2x80x94C6 alkyl, halogen, C1-C6 alkyl, xe2x80x94SC1xe2x80x94C6 alkyl, xe2x80x94CF3, orxe2x80x94OCF3.
Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula I 
heteroaryl, substituted heteroaryl, xe2x80x94NRxe2x80x2Rxe2x80x2, or cycloalkyl;
each Rxe2x80x2 is independently hydrogen or C1-C6 alkyl;
Re is 
xe2x80x83C1-C18 alkyl, heteroaryl, substituted heteroaryl, naphthyl, benzyl, or dansyl;
each of R1, R2, R3, R4, R5, R7, R8, R9, R10, Ra, Rb, Rc, and Rd are independently hydrogen, xe2x80x94OC1xe2x80x94C6 alkyl, xe2x80x94SC1xe2x80x94C6 alkyl, halogen, C1-C6 alkyl, xe2x80x94OH, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94OCF3, xe2x80x94CO2C1xe2x80x94C6 alkyl, xe2x80x94SO3H, xe2x80x94SO3-alkali metal, xe2x80x94NH2, xe2x80x94NHC1xe2x80x94C6 alkyl, 
xe2x80x94CO2C1xe2x80x94C6 alkyl, xe2x80x94SO3H, xe2x80x94SO3 alkali metal, xe2x80x94CN, xe2x80x94CH2-halogen, 
xe2x80x83heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, benzoyl, 
or the pharmaceutically acceptable salts thereof.
Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having inflammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula I 
heteroaryl, substituted heteroaryl, xe2x80x94NRxe2x80x2Rxe2x80x2, or cycloalkyl;
each Rxe2x80x2 is independently hydrogen or C1-C8 alkyl;
Re is 
xe2x80x83C1-C18 alkyl, heteroaryl, substituted
heteroaryl, naphthyl, benzyl, or dansyl;
each of R1, R2, R3, R4, R5, R7, R8, R9, R10, Ra, Rb, Rc, and Rd are independently hydrogen, xe2x80x94OC1xe2x80x94C6 alkyl, xe2x80x94SC1xe2x80x94C6 alkyl, halogen, C1-C6 alkyl, xe2x80x94OH, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94OCF3, xe2x80x94CO2C1xe2x80x94C6 alkyl, xe2x80x94SO3H, xe2x80x94SO3-alkali metal, xe2x80x94NH2, xe2x80x94NHC1xe2x80x94C6 alkyl, 
xe2x80x94CO2C1xe2x80x94C6 alkyl, xe2x80x94SO3H, xe2x80x94SO3 alkali metal, xe2x80x94CN, xe2x80x94CH2-halogen, 
xe2x80x83heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, benzoyl, 
or the pharmaceutically acceptable salts thereof.
The present invention provides a pharmaceutically acceptable composition comprising a compound of Formula I.
Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amount of a compound of Formula I 
heteroaryl, substituted heteroaryl, xe2x80x94NRxe2x80x2Rxe2x80x2, or cycloalkyl;
each Rxe2x80x2is independently hydrogen or C1-C6 alkyl; 
xe2x80x83C1-C18 alkyl, heteroaryl, substituted heteroaryl, naphthyl, benzyl, or dansyl;
each of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Ra, Rb, Rc, and Rd are independently hydrogen, xe2x80x94OC1xe2x80x94C6 alkyl, xe2x80x94SC1xe2x80x94C6 alkyl, halogen, C1-C6 alkyl, xe2x80x94OH, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94OCF3, xe2x80x94CO2C1xe2x80x94C6 alkyl, 
xe2x80x83heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, benzoyl, 
or the pharmaceutically acceptable salts thereof.
Also provided is a method of inhibiting the chemotaxis of monocytes, the method comprising administering to a patient in need of inhibition of chemotaxis of monocytes, a monocyte chemotaxis inhibiting amount of a compound of Formula I 
heteroaryl, substituted heteroaryl, xe2x80x94NRxe2x80x2Rxe2x80x2, or cycloalkyl;
each Rxe2x80x2 is independently hydrogen or C1-C6 alkyl;
Re is 
xe2x80x83C1-C18 alkyl, heteroaryl, substituted heteroaryl, naphthyl, benzyl, or dansyl;
each of R1, R2, R3, R4, R5, R7, R8, R9, R10, Ra, Rb, Rc, and Rd are independently hydrogen, xe2x80x94OC1xe2x80x94C6 alkyl, xe2x80x94SC1xe2x80x94C6 alkyl, halogen, C1-C6 alkyl, xe2x80x94OH, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2H, xe2x80x94OCF3, xe2x80x94CO2C1xe2x80x94C6 alkyl, xe2x80x94SO3H, xe2x80x94SO3-alkali metal, xe2x80x94NH2, xe2x80x94NHC1-C6 alkyl, 
xe2x80x94CO2C1xe2x80x94C6 alkyl, xe2x80x94SO3H, xe2x80x94SO3 alkali metal, xe2x80x94CN, xe2x80x94CH2-halogen, 
xe2x80x83heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, benzoyl, 
and the pharmaceutically acceptable salts thereof.
Also provided by the present invention are compounds having the Formula II 
wherein
Re is phenyl, pyridyl, or substituted phenyl having 1 to 5 substituents selected from halogen, C1-C6 alkyl, OC1xe2x80x94C6 alkyl, xe2x80x94CF3, or xe2x80x94OH;
B is hydrogen, OC1xe2x80x94C6 alkyl, halogen, C1-C6 alkyl, xe2x80x94SC1xe2x80x94C6 alkyl, xe2x80x94OCF3, or xe2x80x94OH;
Y is 
Q is phenyl, pyridyl, or substituted phenyl having from 1 to 5 substituents selected from halogen, xe2x80x94OC1xe2x80x94C6 alkyl, oxazolinyl, xe2x80x94CF2, 
or the pharmaceutically acceptable salts thereof.
In a preferred embodiment of the compounds of Formula II, B is xe2x80x94OCH3 or xe2x80x94OCF3.
In a preferred embodiment of the compounds of Formula II, Re is substituted phenyl.
In a preferred embodiment of the compounds of Formula II, Y is 
In a preferred embodiment of the compounds of Formula II, B is xe2x80x94OCH3, or xe2x80x94OCF3; Re is substituted phenyl and Y is 
Also provided are compounds having the Formula III 
wherein
Re is pyridyl, or phenyl that is substituted with from 1 to 5 substituents selected from halogen, xe2x80x94CF3, xe2x80x94NO2, benzoyl, xe2x80x94SO3 alkali metal,
xe2x80x83C1-C6 alkyl, xe2x80x94OC1xe2x80x94C6 alkyl, xe2x80x94CN, xe2x80x94COOH, 
SO3H, xe2x80x94OCF3, 
xe2x80x94SO2NH2, N(C1-C6 alkyl)2, or xe2x80x94SONH2;
B is OC1xe2x80x94C6 alkyl, hydrogen, halogen, or C1-C6 alkyl; 
Q is phenyl, pyridyl, or phenyl substituted with 1 to 5 substituents selected from halogen, xe2x80x94OC1xe2x80x94C6 alkyl, halogen, or C1-C6 alkyl, or the pharmaceutically acceptable salts thereof.
In a preferred embodiment of the compounds of Formula III, Re is substituted phenyl.
In a preferred embodiment of the compounds of Formula III, B is xe2x80x94OCH3 or xe2x80x94OCF3, or fluorine.
In a preferred embodiment of the compounds of Formula III, 
In a preferred embodiment of the compounds of Formula III, Re is substituted phenyl, B is xe2x80x94OCH3, xe2x80x94OCF3, and Y is 
Also provided are compounds having the Formula IV 
xe2x80x83wherein
X is xe2x80x94NHCH2xe2x80x94, xe2x80x94Oxe2x80x94, 
B is xe2x80x94OC1xe2x80x94C6 alkyl, hydrogen, or xe2x80x94OH;
Re is phenyl, pyridyl, or phenyl substituted with 1 to 5 substituents selected from halogen, xe2x80x94OC1xe2x80x94C6 alkyl, xe2x80x94OH, xe2x80x94NH2, xe2x80x94NHC1xe2x80x94C6 alkyl, 
xe2x80x83xe2x80x94NO2, xe2x80x94C1-C6 alkyl, naphthyl, xe2x80x94CF3, xe2x80x94OCF3, 
xe2x80x94CO2C1xe2x80x94C6 alkyl, furyl, CN, xe2x80x94CO2H, or phenyl; 
Q is phenyl, pyridyl, or substituted phenyl, wherein the substituted phenyl may contain 1 to 5 substituents selected from those listed for Re, or the pharmaceutically acceptable salts thereof.
In a preferred embodiment of the compounds of Formula IV, Re is substituted phenyl.
In a preferred embodiment of the compounds of Formula IV, B is xe2x80x94OCH3.
In a preferred embodiment of the compounds of Formula IV, X is xe2x80x94NHCH2xe2x80x94.
In a preferred embodiment of the compounds of Formula IV, 
In a preferred embodiment of the compounds of Formula IV, Re is substituted phenyl; B is xe2x80x94OCH3; X is xe2x80x94NHCH2xe2x80x94; and 
Also provided are compounds having the Formula V 
B is xe2x80x94OC1xe2x80x94C6 alkyl or halogen;
A is phenyl, C1-C18 alkyl, pyridyl, quinolinyl substituted phenyl, thiazolyl, substituted thiazolyl, substituted pyridyl, substituted quinolinyl, imidazolyl, substituted imidazolyl, naphthyl, substituted naphthyl, benzyl, thienyl, substituted thienyl, isoxazolyl, or substituted isoxazolyl, wherein the substituents are selected from halogen,
xe2x80x83xe2x80x94OC1xe2x80x94C6 alkyl, xe2x80x94NO2, C1-C6 alkyl, xe2x80x94CF3, 
xe2x80x83xe2x80x94NH2, xe2x80x94NHC1xe2x80x94C6 alkyl, 
xe2x80x83xe2x80x94CN, or xe2x80x94CH2-halogen;
Y is 
xe2x80x83xe2x80x94CH2NHxe2x80x94, or xe2x80x94NH2CHxe2x80x94;
xe2x80x83and
C is phenyl or substituted phenyl, pyridyl or substituted pyridyl, wherein the substituents are as described for A, or the pharmaceutically acceptable salts thereof.
In a preferred embodiment of the compounds of Formula V, A is C1-C18 alkyl, substituted phenyl, or thienyl.
In a preferred embodiment of the compounds of Formula V, B is xe2x80x94OCH3 or halogen.
In a preferred embodiment of the compounds of Formula V, Y is 
or xe2x80x94CH2NHxe2x80x94.
In a preferred embodiment of the compounds of Formula V, A is C1-C18 alkyl, substituted phenyl or thienyl; B is xe2x80x94OCF3 or halogen; and Y is 
or xe2x80x94CH2NHxe2x80x94.
Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula VI 
wherein Q is 
each R5 is independently hydrogen or C1-C6 alkyl;
R1, R2, R3, and R4 are independently hydrogen, xe2x80x94SC1xe2x80x94C6 alkyl, xe2x80x94OCF3, xe2x80x94OH, halogen, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94COOR5, xe2x80x94SO3NR5R5, xe2x80x94CHO, xe2x80x94OC1xe2x80x94C6 alkyl, xe2x80x94NR5R5, C1-C6 alkyl, heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, or the pharmaceutically acceptable salts thereof.
Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having inflammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula VI 
wherein Q is 
each R5 is independently hydrogen or C1-C6 alkyl;
R1, R2, R3, and R4 are independently hydrogen, xe2x80x94SC1xe2x80x94C6 alkyl, xe2x80x94OH, halogen, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94COOR5, xe2x80x94S3NR5R5,xe2x80x94CHO,xe2x80x94OCF3, xe2x80x94OC1xe2x80x94C6 alkyl, xe2x80x94NR5R5, C1-C6 alkyl, heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, or the pharmaceutically acceptable salts thereof.
Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amount of a compound of Formula VI 
wherein Q is 
each R5 is independently hydrogen or C1-C6 alkyl;
R1, R2, R3, and R4 are independently hydrogen, xe2x80x94SC1xe2x80x94C6 alkyl, xe2x80x94OH, halogen, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94COOR5, xe2x80x94SO3NR5R5, xe2x80x94CHO, xe2x80x94OCF3, xe2x80x94OC1xe2x80x94C6 alkyl, xe2x80x94NR5R5, C1-C6 alkyl, heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, or the pharmaceutically acceptable salts thereof.
Also provided is a method of inhibiting the chemotaxis of monocytes, the method comprising administering to a patient in need of inhibition of chemotaxis of monocytes a chemotaxis inhibiting amount of a compound of Formula VI 
wherein Q is 
each R5 is independently hydrogen or C1-C6 alkyl;
R1, R2, R3, and R4 are independently hydrogen, xe2x80x94SC1xe2x80x94C6 alkyl, xe2x80x94OH, halogen, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94COOR5, xe2x80x94CHO, xe2x80x94OCF3, xe2x80x94OC1xe2x80x94C6 alkyl, xe2x80x94NR5R5, C1-C6 alkyl, heteroaryl, substituted heteroaryl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, or the pharmaceutically acceptable salts thereof.
The present invention also provides compounds having the Formula VII 
wherein 
Rz is phenyl or phenyl substituted with from 1 to 5 substituents selected from halogen or xe2x80x94CF3; or
X and Rz are xe2x80x94N(SO2-3,5-dichlorophenyl)2, or the pharmaceutically acceptable salts thereof.
The present invention also provides compounds having the Formula VIII 
wherein 
Rz is phenyl, pyridyl, or phenyl substituted with from 1 to 5 substituents wherein the substituents are selected from halogen, pyridyl, or xe2x80x94CO2C1-C6 alkyl.
Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula II.
Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having inflammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula II.
Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amount of a compound of Formula II.
Also provided is a method of inhibiting the chemotaxis of monocytes, the method comprising administering to a patient in need of inhibition of chemotaxis of monocytes a chemotaxis inhibiting amount of a compound of Formula II.
The present invention provides a pharmaceutically acceptable composition comprising a compound of Formula II.
Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula III.
Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having inflammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula III.
Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amount of a compound of Formula III.
Also provided is a method of inhibiting the chemotaxis of monocytes, the method comprising administering to a patient in need of inhibition of chemotaxis of monocytes a chemotaxis inhibiting amount of a compound of Formula III.
The present invention also provides a pharmaceutically acceptable composition comprising a compound of Formula III.
Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula IV.
Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having inflammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula IV.
Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amount of a compound of Formula IV.
Also provided is a method of inhibiting the chemotaxis of monocytes, the method comprising administering to a patient in need of inhibition of chemotaxis of monocytes a chemotaxis inhibiting amount of a compound of Formula IV.
The present invention provides a pharmaceutically acceptable composition comprising a compound of Formula IV.
Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula V.
Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having inflammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula V.
Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amount of a compound of Formula V.
Also provided is a method of inhibiting the chemotaxis of monocytes, the method comprising administering to a patient in need of inhibition of chemotaxis of monocytes a chemotaxis inhibiting amount of a compound of Formula V.
The present invention also provides a pharmaceutically acceptable composition comprising a compound of Formula V.
Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula VII.
Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having inflammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula VII.
Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amount of a compound of Formula VII.
Also provided is a method of inhibiting the chemotaxis of monocytes, the method comprising administering to a patient in need of inhibition of chemotaxis of monocytes a chemotaxis inhibiting amount of a compound of Formula VII.
The present invention also provides a pharmaceutically acceptable composition comprising a compound of Formula VII.
Also provided is a method of treating or preventing atherosclerosis, the method comprising administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula VIII.
Also provided is a method of treating or preventing inflammation, the method comprising administering to a patient having inflammation or at risk of having inflammation a therapeutically effective amount of a compound of Formula VIII.
Also provided is a method of inhibiting 15-lipoxygenase, the method comprising administering to a patient in need of 15-lipoxygenase inhibition a 15-lipoxygenase inhibiting amount of a compound of Formula VIII.
Also provided is a method of inhibiting the chemotaxis of monocytes, the method comprising administering to a patient in need of inhibition of chemotaxis of monocytes a chemotaxis inhibiting amount of a compound of Formula VIII.
The present invention provides a pharmaceutically acceptable composition comprising a compound of Formula VIII.
The present invention provides the compounds:
3-Amino-4-methoxy-N-(3,4-dichlorophenyl)-benzamide;
3-(3-Trifluoromethyl-phenylamino)-4-methoxy-N-(4-fluorophenyl)-benzamide;
3-[3-(3,5-Dichlorophenyl)-thioureido]-4-methoxy-N-phenyl-benzamide;
4-[3-(2-Methoxy-5-phenylcarbamoyl-phenyl)-thioureido]-benzoic acid;
4-Methoxy-N-phenyl-3-(3-pyridin-3-yl-thioureido)-benzamide;
3-[3-(3,5-Dichlorophenyl)-thioureido]-N-(4-fluorophenyl)-4-methoxy-benzamide;
3-(3,5-Dichloro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide; or
3-Methanesulfonylamino-4-methoxy-N-(3,4-dichlorophenyl)-benzamide.
The present invention provides the compounds:
3-Amino-4-methoxy-N-(4-chlorophenyl)-benzamide;
3-Amino-4-methoxy-N-(3,4-dimethylphenyl)-benzamide;
3-Amino-4-methoxy-N-(4-methylphenyl)-benzamide;
3-Amino-4-methoxy-N-(4-fluorophenyl)-benzamide;
3-Amino-4-fluoro-N-phenyl-benzamide; or
3-Amino-4-ethoxy-N-phenyl-benezamide
The present invention provides the compounds:
3-Amino-4-methoxy-N-(3,5-dimethylphenyl)-benzamide;
3-Amino-4-methoxy-N-(3-chloro-4-methylphenyl)-benzamide;
3-Amino-4-methoxy-N-(2,4-difluorophenyl)-benzamide;
3-Amino-4-methoxy-N-(3,4-difluorophenyl)-benzamide;
3-Amino-4-methoxy-N-(3-chlorophenyl)-benzamide;
3-Amino-4-ethyl-N-phenyl-benzamide;
3-Amino-4-ethyl-N-(3,4-dichlorophenyl)-benzamide;
3-Amino-4-ethyl-N-(3,4-difluorophenyl)-benzamide; or
3-Amino-4-methylsulfanyl-N-phenyl-benzamide.
The present invention provides the compounds:
N-(3-Amino-4-methoxyphenyl)-benzamide;
3,4-Dichloro-N-(3-amino-4-fluorophenyl)- benzamide;
3,4-Dichloro-N-(3-amino-4-methoxy-phenyl)-benzamide;
3-Phenylamino -N-phenyl-benzamide;
3-(3,5-Dichloro-phenylamino)-N-phenyl-benzamide;
3-(2-Methoxy-phenylamino)-N-phenyl-benzamide;
4-Methoxy-3-phenylamino-N-phenyl-benzamide;
3-(2-Methoxy-phenylamino)-4-methoxy-N-phenyl-benzamide; or
3-(3-Trifluoromethyl-phenylamino)-4-methoxy-N-phenyl-benzamide.
The present invention provides the compounds:
3-(3-Chloro-phenylamino)-4-methoxy-N-phenyl-benzamide;
3-(3-Methyl-phenylamino)-4-methoxy-N-phenyl-benzamide;
3-(3-Nitro-phenylamino)-4-methoxy-N-phenyl-benzamide;
3-(4-Methyl-phenylamino)-4-methoxy-N-phenyl-benzamide;
3-(3,5-Dichloro-phenylamino)-4-methoxy-N-phenyl-benzamide;
3-(3,5-Dimethyl-phenylamino)-4-methoxy-N-phenyl-benzamide;
3-Phenylamino-4-fluoro-N-phenyl-benzamide;
3-Phenylamino-4-methyl-N-phenyl-benzamide; or
3-Phenylamino-4-methoxy-N-(4-fluorophenyl)-benzamide.
The present invention provides the compounds:
4-Ethyl-3-(3-trifluoromethyl-phenylamino)-N-phenyl-benzamide;
4-Ethoxy-3-(3-trifluoromethyl-phenylamino)-N-phenyl-benzamide;
4-Methylsulfanyl-3-(3-trifluoromethyl-phenylamino)-N-phenyl-benzamide;
3-[4-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-phenylamino]-4-methoxy-N-phenyl-benzamide;
4-Methoxy-3-(3-trifluoromethyl-phenylamino)-N-(3-pyridyl)-benzamide;
4-Methoxy-3-(3,5-dimethyl-phenylamino)-N-(4-fluorophenyl)-benzamide;
4-Methoxy-3-(3-trifluoromethyl-phenylamino)-N-(3,4-dichlorophenyl)-benzamide;
4-Methoxy-3-(3-trifluoromethyl-phenylamino)-N-(3,4-difluorophenyl)-benzamide;
N-[3-(Phenylamino)-4-methoxy-phenyl]-benzamide; or
3-Benzylamino-4-methoxy-N-phenyl-benzamide.
The present invention provides the compounds:
3-(3,5-Dichloro-benzylamino)-4-methoxy-N-phenyl-benzamide;
3-(3,4-Dimethoxy-benzylamino)-4-methoxy-N-phenyl-benzamide;
3-Phenoxy-N-phenyl-benzamide;
3-Phenoxy-4-methoxy-N-phenyl-benzamide;
3-(Phenylamino)-4-methoxy-benzoic acid, phenyl ester;
4-Hydroxy-3-(3,5-dichloro-phenylamino)-N-phenyl-benzamide;
3-(3,5-Dichloro-phenylamino)-4-hydroxy-N-(4-methoxyphenyl)-benzamide;
3-(3,5-Dichloro-phenylamino)-4-hydroxy-N-(4-methylphenyl)-benzamide; or
3-(3,5-Dichloro-phenylamino)-4-hydroxy-N-(3-hydroxy-4-methoxyphenyl)-benzamide.
The present invention provides the compounds:
3-[3-(3-Chlorophenyl)-thioureido]-4-methoxy-N-phenyl-benzamide;
4-Methoxy-N-phenyl-3-(3-phenyl-thioureido)-benzamide;
4-Methoxy-N-phenyl-3-[3-(4-trifluoromethyl-phenyl)-thioureido]-benzamide;
3-[3-(4-tert-Butyl-phenyl)-thioureido]-4-methoxy-N-phenyl-benzamide;
3-[3-(4-Chlorophenyl)-thioureido]-4-methoxy-N-phenyl-benzamide;
3-[3-(3-Nitrophenyl)-thioureido]-4-methoxy-N-phenyl-benzamide;
4-Methoxy-N-phenyl-3-(3-benzoyl-thioureido)-benzamide;
4-Methoxy-N-phenyl-3-[3-(2,3,5,6-tetrafluoro-phenyl)-thioureido]-benzamide;
4-Methoxy-N-phenyl-3-(-3-p-tolyl-thioureido)-benzamide; or
3-[3-(3,5-Dichlorophenyl)-thioureido]-N-phenyl-benzamide.
The present invention provides the compounds:
3-[3-(3,5-Dichlorophenyl)-thioureido]-4-methyl-N-phenyl-benzamide;
3-[3-(3,4-Dimethoxyphenyl)-thioureido]-4-methoxy-N-phenyl-benzamide;
3-[3-(4-Chloro-3-trifluoromethylphenyl)-thioureido]-4-methoxy-N-phenyl-benzamide;
3-[3-(3-Cyanophenyl)-thioureido]-4-methoxy-N-phenyl-benzamide;
3-[3-(3-Acetyl-phenyl)-thioureido]-4-methoxy-N-phenyl-benzamide;
3-[3-(4-Chloro-3-nitrophenyl)-thioureido]-4-methoxy-N-phenyl-benzamide;
3-[3-(4-Fluorophenyl)-thioureido]-4-methoxy-N-phenyl-benzamide;
3-[3-(3,5-Dichlorophenyl)-thioureido]-4-methoxy-N-(4-methoxy-phenyl)-benzamide; or
3-[3-(3,5-Dichlorophenyl)-thioureido]-4-ethoxy-N-phenyl-benzamide.
The present invention provides the compounds:
4-[3-(2-Methoxy-5-phenylcarbamoyl-phenyl)-thioureido]-benzenesulfonic acid;
4-Methoxy-3-[3-(4-methoxy-phenyl)-thioureido]-N-phenyl-benzamide;
4-Methoxy-N-phenyl-3-[3-(3-trifluoromethyl-phenyl)-thioureido]-benzamide;
3-[3-(3,4-Dichlorophenyl)-thioureido]-4-methoxy-N-phenyl-benzamide;
1-{3-[3-(3,5-Dichlorophenyl)-thioureido]-4-methoxyphenyl}-3-phenyl-urea;
N-{3-[3-(3,5-Dichlorophenyl)-thioureido]-4-methoxy-phenyl}-benzamide;
4-Methoxy-3-[3-(4-nitrophenyl)-thioureido]-N-phenyl-benzamide;
3-[3-(3,5-Bis-trifluoromethylphenyl)-thioureido]-4-methoxy-N-phenyl-benzamide; or
4-Methoxy-N-phenyl-3-[3-(4-sulfamoyl-phenyl)-thioureido]-benzamide.
The present invention provides the compounds:
N-(4-Chlorophenyl)-3-[3-(3,5-dichlorophenyl)-thioureido]-4-methoxy-benzamide;
3-[3-(4-Dimethylaminophenyl)-thioureido]-4-methoxy-N-phenyl-benzamide;
3-[3-(3,5-Dichlorophenyl)-thioureido]-4-methoxy-N-p-tolyl-benzamide;
4-Methoxy-N-phenyl-3-(3-m-tolyl-thioureido)-benzamide;
3-[3-(3,5-Dichlorophenyl)-thioureido]-4-fluoro-N-phenyl-benzamide;
N-(3,4-Dichlorophenyl)-3-[3-(3,5-dichlorophenyl)-thioureido]4-methoxy-benzamide;
4-Methoxy-N-phenyl-3-(3-o-tolyl-thioureido)-benzamide;
3-[3-(3,5-Dimethylphenyl)-thioureido]-4-methoxy-N-phenyl-benzamide; or
3-[3-(3,4-Dichlorophenyl)-thioureido]-4-methoxy-N-pyridin-3-yl-benzamide.
The present invention provides the compounds:
5-[3-(3,5-Dichlorophenyl)-thioureido]-2-fluoro-N-phenyl-benzamide;
N-(3,4-Dimethylphenyl)-4-methoxy-3(3m-tolyl-thioureido)-benzamide;
N-(3,5-Dimethylphenyl)-4-methoxy-3-(3-m-tolyl-thioureido)-benzamide;
N-(3-Chloro-4-methylphenyl)-3-[3-(3,5-dichlorophenyl)-thioureido]-4-methoxy-benzamide;
N-(3,4-Dichlorophenyl)-4-methoxy-3-[3-(4-sulfamoyl-phenyl)-thioureido]-benzamide;
3-[3-(3,5-Dichlorophenyl)-thioureido]-4-methylsulfanyl-N-phenyl-benzamide;
3-[3-(3,5-Dichlorophenyl)-thioureido]-N-(3,4-difluoro-phenyl)-4-methoxy-benzamide;
N-(3-Chlorophenyl)-3-[3-(4-fluorophenyl)-thioureido]-4-methoxy-benzamide;
3-[3-(3,5-Dichlorophenyl)-thioureido]-4-methoxy-N-phenyl-benzenesulfonamide; or
4-Ethyl-N-phenyl-3-[3-(3-trifluoromethylphenyl)-thioureido]-benzamide.
The present invention provides the compounds:
4-Ethyl-N-(3,4-difluorophenyl)-3-[3-(3-trifluoromethyl-phenyl)-thioureido]-benzamide;
3-{3-[2-Methoxy-5-(pyridin-3-ylcarbamoyl)-phenyl]-thioureido}-benzoic acid;
3-[3-(2-Methoxy-5-phenylcarbamoyl-phenyl)-thioureido]-benzoic acid;
3,4-Dichloro-N-{4-fluoro-3-[3-(3-trifluoromethylphenyl)-thioureido]-phenyl}-benzamide;
3,4-Dichloro-N-{3-[3-(3,5-dichlorophenyl)-thioureido]-4 -methoxyphenyl}-benzamide;
3-(3,5-Dichloro-benzenesulfonylamino)-4-methoxy-N-(3, 4-difluorophenyl)-benzamide;
3-(3,5-Dichloro-benzenesulfonylamino)-4-methoxy-N-(3,4-dichlorophenyl)-benzamide; or
3-Benzenesulfonylamino-4-methoxy-N-phenyl-benzamide.
The present invention provides the compounds:
3-(4-Methoxy-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(3-Nitro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(3-Chloro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(4-Methyl-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(4-Fluoro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(4,5-Dibromo-thiophene-2-sulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(2-Chloro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(4-Trifluoromethyl-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(Butane-1-sulfonylamino)-4-methoxy-N-phenyl-benzamide; or 3-(Quinoline-8-sulfonylamino)-4-methoxy-N-phenyl-benzamide.
The present invention provides the compounds:
3-(2-Acetylamino-4-methyl-thiazole-5-sulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(2,5-Dichloro-thiophene-3-sulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(Naphthalene-1-sulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-Ethanesulfonylamino-4-methoxy-N-phenyl-benzamide;
3-Phenylmethanesulfonylamino-4-methoxy-N-phenyl-benzamide;
3-(3,4-Dichloro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(2,4-Difluoro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(Toluene-3-sulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(4-Acetylamino-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(Naphthalene-2-sulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(1-Methyl-1H-imidazole-4-sulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(Thiophene-2-sulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(5-Dimethylamino-naphthalene-1-sulfonylamino)-4-methoxy-N-phenyl-benzamide;
2-Methoxy-5-phenylcarbamoyl-carbonic acid-phenyl ester phenyl ester; or
4-Hydroxy-3-phenylamino-N-phenyl-benzamide.
The present invention provides the compounds:
3-(3-Amino-4-methoxy-benzoylamino)-benzoic acid ethyl ester;
3-(3-Amino-4-methoxy-benzoylamino)-benzoic acid methyl ester;
3,4-Difluoro-N-(3-amino-4-methoxy-phenyl)-benzamide;
3,4-Difluoro-N-(3-amino-4-fluoro-phenyl)-benzamide;
1-(3-Amino-4-methoxy-phenyl)-3-(3,4-dichloro-phenyl)-urea;
3-(4-Fluoro-phenylamino)-4-methoxy-N-phenyl-benzamide; or
3-(3,5-Dichloro-phenylamino)-4-methoxy-N-(4-fluoro-phenyl)-benzamide.
The present invention provides the compounds:
3-(4-Fluoro-phenylamino)-4-methoxy-N-(4-fluoro-phenyl)-benzamide;
3-[4-Methoxy-3-(3-trifluoromethyl-phenylamino)-benzoylamino]-benzoic acid methyl ester;
3-[4-Methoxy-3-(3-trifluoromethyl-phenylamino)-benzoylamino]-benzoic acid ethyl ester;
4-Trifluoromethoxy-3-(3-trifluoromethyl-phenylamino)-N-phenyl-benzamide;
4-Trifluoromethoxy-3-(3-trifluoromethyl-phenylamino)-N-(4-fluoro-phenyl)-benzamide;
3,4-Dichloro-N-[4-methoxy-3-(3-trifluoromethyl-phenylamino)-phenyl]-benzamide;
3-[3-(2-Methoxy-5-phenylcarbamoyl-phenyl)-thioureido]-benzoic acid methyl ester;
3-{3-[5-(3,4-Difluoro-phenylcarbamoyl)-2-methoxy-phenyl]-thioureido}-benzoic acid;
3-[3-(3,5-Dichloro-phenyl)-thioureido]-4-trifluoromethoxy-N-(4-fluoro-phenyl)-benzamide; or
3-[3-(3-trifluoromethyl-phenyl)-thioureido]-4-trifluoromethoxy-N-(4-fluoro-phenyl)-benzamide.
The present invention provides the compounds:
4-{3-[5-(3,4-Difluoro-phenylcarbamoyl)-2-methoxy-phenyl]-thioureido}-benzenesulfonic acid;
4-{3-[5-(4-Fluoro-phenylcarbamoyl)-2-methoxy-phenyl]-thioureido}-benzoic acid;
3-{3-[5-(4-Fluoro-phenylcarbamoyl)-2-methoxy-phenyl]-thioureido}-benzoic acid;
4-{3-[5-(3,4-Difluoro-benzoylamino)-2-methoxy-phenyl]-thioureido}-benzoic acid;
3-{3-[5-(3,4-Difluoro-benzoylamino)-2-methoxy-phenyl]-thioureido}-benzoic acid;
N-{3-[3-(3,5-Dichloro-phenyl)-thioureido]-4-fluoro-phenyl}-3,4-difluoro-benzamide;
1-(3,4-Dichloro-phenyl)-3-{3-[3-(3,5-dichloro-phenyl)-thioureido]-4-methoxy-phenyl}-urea;
3-(3-{5-[3-(3,4-Dichloro-phenyl)-ureido]-2-methoxy-phenyl}-thioureido)-benzoic acid methyl ester;
3-(3-{5-[3-(3,4-Dichloro-phenyl)-ureido]-2-methoxy-phenyl}-thioureido)-benzoic acid; or
1-{3-[3-(3,5-Bis-trifluoromethyl-phenyl)-thioureido]-4-methoxy-phenyl}-3-(3,4-dichloro-phenyl)-urea.
The present invention provides the compounds:
1-{3-[3-(4-Chloro-3-nitro-phenyl)-thioureido]-4-methoxy-phenyl}-3-(3,4-dichloro-phenyl)-urea;
3-[3-(3,5-Dichloro-phenyl)-thioureido]-4-methoxy-benzoic acid benzyl ester;
3-(Dodecane-1-sulfonylamino)-4-methoxy-N-phenyl-benzamide;
4-Methoxy-3-(octane-1-sulfonylamino)-N-phenyl-benzamide;
3-(Decane-1-sulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(3-Nitro-benzenesufonylamino)-4-methoxy-N-(3,4-difluoro-phenyl)-benzamide;
3,5-Dichloro-N-{5-[3-(3,4-dichloro-phenyl)-ureido]-2-methoxy-phenyl}-benzenesulfonamide;
3-(1-Methylethyl-1-sulfonylamino)-4-methoxy-N-phenyl-benzamide;
4-(2-Methoxy-5-phenylcarbamoyl-phenylsulfamoyl)-benzoic acid; or
3-(Octadecane-1-sulfonylamino)-4-methoxy-N-phenyl-benzamide.
The present invention provides the compounds:
3-(3-Amino-benzenesulfonylamino)-4-methoxy-N-(3,4-difluoro-phenyl)-benzamide;
4-Methoxy-3-(4-nitro-benzenesulfonylamino)-N-(3,4-difluoro-phenyl)-benzamide;
3-(4-Cyano-benzenesulfonylamino)-4-methoxy-N-(3,4-difluoro-phenyl)-benzamide;
4-Methoxy-3-(4-nitro-benzenesulfonylamino)-N-phenyl-benzamide;
3-(3-Cyano-benzenesulfonylamino)-4-methoxy-N-(4-fluoro-phenyl)-benzamide;
4-Methoxy-3-(3-nitro-benzenesulfonylamino)-N-(4-fluoro-phenyl)-benzamide;
4-Methoxy-3-(4-nitro-benzenesulfonylamino)-N-(4-fluoro-phenyl)-benzamide;
3-(4-Cyano-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-(4-Cyano-benzenesulfonylamino)-4-methoxy-N-(4-fluoro-phenyl)-benzamide; or
3-(Dodecane-1-sulfonylamino)-4-methoxy-N-(3,4-dichloro-phenyl)-benzamide.
The present invention provides the compounds:
3-(3-Cyano-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide;
3,4-Dichloro-N-[4-methoxy-3-(4-methoxy-benzenesulfonylamino)-phenyl]-benzamide;
3,4-Dichloro-N-[4-methoxy-3-(toluene-4-sulfonylamino)-phenyl]-benzamide;
3,4-Difluoro-N-[4-methoxy-3-(3-amino-benzenesulfonylamino)-phenyl]-benzamide;
3,4-Difluoro-N-[4-methoxy-3-(4-amino-benzenesulfonylamino)-phenyl]-benzamide;
3,4-Difluoro-N-[4-methoxy-3-(1-dodecane-sulfonylamino)-phenyl]-benzamide;
3,4-Difluoro-N-[4-methoxy-3-(chloromethyl-sulfonylamino)-phenyl]-benzamide;
3,4-Difluoro-N-[4-methoxy-3-(4-nitro-benzenesulfonylamino)-phenyl]-benzamide;
3,4-Difluoro-N-[4-methoxy-3-(3-nitro-benzenesulfonylamino)-phenyl]-benzamide; or
3,4-Difluoro-N-[3-(4-cyano-benzenesulfonylamino)-4-methoxy-phenyl]-benzamide.
The present invention provides the compounds:
3,4-Difluoro-N-[3-(3-cyano-benzenesulfonylamino)-4-methoxy-phenyl]-benzamide;
3,4-Difluoro-N-[4-fluoro-3-(thiophene-2-sulfonylamino)-phenyl]-benzamide;
Thiophene-2-sulfonic acid {5-[3-(3,4-dichloro-phenyl)-ureido]-2-methoxy-phenyl}-amide;
3-(3,5-Dichloro-benzenesulfonylamino)-4-methoxy-N-phenyl-thiobenzamide;
3,5-Dichloro-N-(2-methoxy-5-phenylaminomethyl-phenyl)-benzenesulfonamide;
3-(3-Hydroxy-benzylamino)-4-methoxy-N-(3,4-difluoro-phenyl)-benzamide;
3-(4-Diethylamino-benzylamino)-4-methoxy-N-phenyl-benzamide;
3-(3-Fluoro-benzylamino)-4-methoxy-N-(3,4-difluoro-phenyl)-benzamide;
3-(3-Hydroxy-benzylamino)-4-methoxy-N-phenyl-benzamide; or
4-Methoxy-3-(3-fluoro-benzylamino)-N-phenyl-benzamide.
The present invention provides the compounds:
4-Methoxy-3-(3-nitro-benzylamino)-N-phenyl-benzamide;
4-Methoxy-3-(4-methoxy-benzylamino)-N-phenyl-benzamide;
4-Methoxy-3-[(naphthalen-1-ylmethyl)-amino]-N-phenyl-benzamide;
4-Methoxy-3-(3,5xe2x80x94dimethyl-benzylamino)-N-phenyl-benzamide;
3-(2,3-Difluoro-benzylamino)-4-methoxy-N-phenyl-benzamide;
Acetic acid 4-[(2-methoxy-5-phenylcarbamoyl-phenylamino)-methyl]-phenyl ester;
4-[(2-Methoxy-5-phenylcarbamoyl-phenylamino)-methyl]-benzoic acid methyl ester;
3-[(Furan-3-ylmethyl)-amino]-4-methoxy-N-phenyl-benzamide;
4-Methoxy-3-(2-methyl-benzylamino)-N-phenyl-benzamide; or
4-Methoxy-3-(4-fluoro-benzylamino)-N-phenyl-benzamide.
The present invention provides the compounds:
3-(4-Hydroxy-3-nitro-benzylamino)-4-methoxy-N-phenyl-benzamide;
3-(4-Diethylamino-benzylamino)-4-methoxy-N-(3,4-difluoro-phenyl)-benzamide;
3-Benzylamino-4-methoxy-N-(3,4-difluoro-phenyl)-benzamide;
3-(3-Hydroxy-4-nitro-benzylamino)-4-methoxy-N-phenyl-benzamide;
3-(3-Cyano-benzylamino)-4-methoxy-N-phenyl-benzamide;
3-{[5-(3,4-Difluoro-phenylcarbamoyl)-2-methoxy-phenylamino]-methyl}-benzoic acid;
3-(3-Chloro-benzylamino)-4-methoxy-N-phenyl-benzamide;
3-(4-tert-Butyl-benzylamino)-4-methoxy-N-phenyl-benzamide;
3-(4-Cyano-benzylamino)-4-methoxy-N-phenyl-benzamide; or
4-{[5-(3,4-Difluoro-phenylcarbamoyl)-2-methoxy-phenylamino]-methyl}-benzoic acid.
The present invention provides the compounds:
4-Methoxy-3-(4-propoxy-benzylamino)-N-phenyl-benzamide;
3-[(Biphenyl-4-ylmethyl)-amino]-4-methoxy-N-phenyl-benzamide;
4-Methoxy-3-(4-methyl-benzylamino)-N-phenyl-benzamide;
4-Methoxy-3-(2-methoxy-benzylamino)-N-phenyl-benzamide;
3-(4-Butyl-benzylamino)-4-methoxy-N-phenyl-benzamide;
3-(3-Fluoro-benzylamino)-4-methoxy-N-(3,4-dichloro-phenyl)-benzamide;
3-[(2-Methoxy-5-phenylcarbamoyl-phenylamino)-methyl]-benzoic acid;
3-(3,4-Dimethyl-benzylamino)-4-methoxy-N-phenyl-benzamide;
3-(4-Isopropyl-benzylamino)-4-methoxy-N-phenyl-benzamide; or
3,4-Dichloro-N-[3-(3-fluoro-benzylamino)-4-methoxy-phenyl]-benzamide.
The present invention provides the compounds:
3,4-Difluoro-N-[3-(3-hydroxy-benzylamino)-4-methoxy-phenyl]-benzamide;
3-{[5-(3,4-Difluoro-benzoylamino)-2-methoxy-phenylamino]-methyl}-benzoic acid;
3-[3-(3,5-Dichloro-phenyl)-thioureidomethyl]-4-methoxy-N-phenyl-benzamide;
3-(3,5-Dichloro-benzenesulfonylamino)-4-methoxy-N-phenyl-benzamide;
3-[(3,5-Dichloro-benzenesulfonylamino)-methyl]-4-methoxy-N-phenyl-benzamide;
4-Methoxy-3-phenylmethanesulfonylamino-N-phenyl-benzamide;
3-[Bis[(3,5-dichlorophenyl)sulfonyl]amino]-4-methoxy-N-phenyl-benzamide;
(2-Methoxy-5-phenylcarbamoyl-phenylcarbamoyl)-acetic acid phenylmethyl ester;
4-Methoxy-N-phenyl-3-[2-(3-trifluoromethyl-phenyl)-ethylamino]-benzamide; or
4-Methoxy-3-[3-(3-nitro-phenyl)-thioureido]-N-phenyl-benzamide.
The present invention provides the compounds:
3-[(3,5-Dichlorobenzoyl)amino]-4-methyl-N-phenyl-benzamide;
3-[[(Cyanoimino)[(3,5-dichlorophenyl)amino]methyl]amino]-4-methoxy-N-phenyl-benzamide;
3-(2-Hydroxy-2-phenyl-acetylamino)-4-methoxy-N-phenyl-benzamide;
4-Methoxy-3-[(thiophen-2-ylmethyl)-amino]-N-(3,4-difluoro-phenyl)-benzamide;
4-Methoxy-3-[(thiophen-2-ylmethyl)-amino]-N-phenyl-benzamide;
4-Methoxy-3-[(thiophen-2-ylmethyl)-amino]-N-(4-fluoro-phenyl)-benzamide;
4-Methoxy-3-[(thiophen-2-ylmethyl)-amino]-N-(3,4-dichloro-phenyl)-benzamide;
4-Methoxy-3-[(thiophen-2-ylmethyl)-amino]-N-pyridin-3-yl-benzamide;
4-{4-Methoxy-3-[(thiophen-2-ylmethyl)-amino]-benzoylamino}-benzoic acid ethyl ester;
3,4-Dichloro-N-{4-methoxy-3-[(thiophen-2-ylmethyl)-amino]-phenyl}-benzamide; or
3,4-Difluoro-N-{4-methoxy-3-[(thiophen-2-ylmethyl)-amino]-phenyl}-benzamide.
The present invention provides the compounds:
3-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-4-methoxy-N-phenyl-benzamide;
4-Methoxy-3-(3,5-difluoro-benzylamino)-N-phenyl-benzamide;
3-(4-Dimethylamino-benzylamino)-4-methoxy-N-phenyl-benzamide;
4-Methoxy-3-(3-trifluoromethyl-benzylamino)-N-phenyl-benzamide;
4-Methoxy-3-(2-fluoro-benzylamino)-N-phenyl-benzamide;
N-{3-[(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-amino]-4-methoxy-phenyl}-benzamide;
3-(4-Hydroxy-benzylamino)-4-methoxy-N-phenyl-benzamide;
4-Methoxy-3-(3-methyl-benzylamino-N-phenyl-benzamide; or
3-(3,4-Difluoro-benzylamino)-4-methoxy-N-phenyl-benzamide.
The present invention provides the compounds:
3-[(Pyridin-3-ylmethyl)-amino]-4-methoxy-N-phenyl-3-benzamide;
3-[(Pyridin-3-ylmethyl)-amino]-4-methoxy-N-(3,4-difluoro-phenyl)-benzamide;
3-[(Pyridin-3-ylmethyl)-amino]-4-methoxy-N-(3,4-dichloro-phenyl)-benzamide;
4-[(2-Methoxy-5-phenylcarbamoyl-phenylamino)-methyl]-benzoic acid;
3,4-Difluoro-N-{[3-(pyridin-3-ylmethyl)-amino]-4-methoxy-phenyl}-benzamide; or
3-(3-Acetylamino-phenylamino)-4-methoxy-N-phenyl-benzamide.
The term xe2x80x9calkylxe2x80x9d means a straight or branched chain hydrocarbon. Representative examples of alkyl groups are methyl, ethyl, propyl, isopropyl, isobutyl, butyl, tert-butyl, sec-butyl, pentyl, and hexyl. Preferably the alkyl group contains from 1 to 6 carbon atoms.
The term xe2x80x9calkoxyxe2x80x9d means an alkyl group attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy.
The term xe2x80x9chalogenxe2x80x9d includes chlorine, fluorine, bromine, and iodine.
The term xe2x80x9calkenylxe2x80x9d means a branched or straight chain hydrocarbon having one or more carbon-carbon double bond.
The term xe2x80x9carylxe2x80x9d means an aromatic hydrocarbon. Representative examples of aryl groups include phenyl and naphthyl.
The term xe2x80x9cheteroatomxe2x80x9d includes oxygen, nitrogen, and sulfur.
The term xe2x80x9cheteroarylxe2x80x9d means an aryl group wherein one or more carbon atom of the aromatic hydrocarbon has been replaced with a heteroatom. Examples of heteroaryl radicals include, but are not limited to, pyridyl, imidazolyl, pyrrolyl, thienyl, furyl, pyranyl, pyrimidinyl, pyridazinyl, indolyl, quinolyl, naphthyridinyl, and isoxazolyl.
The term xe2x80x9ccycloalkylxe2x80x9d means a cyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term xe2x80x9csubstitutedxe2x80x9d means that the base organic radical has one or more substituents. For example, substituted cyclohexyl means a cyclohexyl radical that has one or more substituents. Substituents include, but are not limited to, halogen, C1-C8 alkyl, xe2x80x94CN, CF3, xe2x80x94NO2, xe2x80x94NH2, xe2x80x94NHC1xe2x80x94C8alkyl, xe2x80x94N(C1-C8alkyl)2, xe2x80x94OC1-C8 alkyl, and xe2x80x94OH.
The term xe2x80x9cheterocyclexe2x80x9d means a cycloalkyl group wherein one or more atom is replaced with a heteroatom. Examples of heterocycles include, but are not limited to, pyrrolidinyl, piperidinyl, and piperazinyl.
The symbol xe2x80x9cxe2x80x94xe2x80x9d means a bond.
The term xe2x80x9cpatientxe2x80x9d means all animals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, and pigs.
Those skilled in the art are easily able to identify patients having atherosclerosis and inflammation.
A therapeutically effective amount is an amount of a compound of the present invention that when administered to a patient ameliorates a symptom of atherosclerosis or inflammation.
The compounds of the present invention can be administered to a patient either alone or as part of a pharmaceutical composition. The compositions can be administered to patients either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracistemally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments or drops), or as a buccal or nasal spray.
Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol and silicic acid, (b) binders, as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft- and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable nonirritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.
The term xe2x80x9cpharmaceutically acceptable salts, esters, amides, and prodrugsxe2x80x9d as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term salts refers to the relatively nontoxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See, for example, S. M. Berge, et al., Pharmaceutical Salts, J. Pharm. Sci., 1977;66:1-19, which is incorporated herein by reference).
Examples of pharmaceutically acceptable, nontoxic esters of the compounds of this invention include C1-C6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-C4 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, nontoxic amides of the compounds of this invention include amides derived from ammonia, primary C1-C6 alkyl amines and secondary C1-C6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5- or 6-membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-C3 alkyl primary amines and C1-C2 dialkyl secondary amines are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
The compounds of the present invention can exist in different stereoisometric forms by virtue of the presence of asymmetric centers in the compounds. It is contemplated that all stereoisometric forms of the compounds as well as mixtures thereof, including racemic mixtures, form part of this invention.
The compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kg of body weight per day is preferable. The specific dosage used, however, can vary. For example, the dosage can depend on a numbers of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to those skilled in the art.
The scope of the present invention includes compounds that are synthesized by standard techniques used organic synthesis and known to those skilled in the art, including combinatorial chemistry, or by biological mechanisms, including digestion and metabolism.
The examples presented below are intended to illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the claims, in any way.